Mechanosensory hair cell loss is the leading cause of human hearing and balance disorders. While new hair cells do not regenerate in humans, this process is common in other animals. Moreover, in some animals there is constant production of hair cells throughout their life, requiring a steady supply of new hair cell precursors. In this R21 application, we propose experiments to identify self-renewing precursors within the zebrafish lateral line system, and screen for mutations that alter precursor function. Lateral line mechanosensory hair cells share many properties with the inner ear, but since they are located on the body surface, they are easily accessible to visualization and manipulation. These experiments take advantage of the zebrafish system, including their rapid development, established genetics and advancing genomics. We propose 2 aims: to identify mutations that alter hair cell regeneration as a first step to uncovering the molecular regulation of this process, and to identify hair cell precursors within the adult lateral line and determine whether they have the self-renewing properties of stem cells. The proposed exploratory research should establish the zebrafish lateral line as a model for hair cell regeneration, and develop genetic resources that will be useful to the research community. Mechanosensory hair cell loss in humans, the leading cause of hearing and balance disorders, is irreversible. In contrast, hair cells regenerate in other animals. Understanding the regulatory mechanisms behind successful regeneration will influence strategies towards recovery of function in humans. [unreadable] [unreadable]